CZ292446B6 - Process for preparing N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide and salts thereof - Google Patents

Abstract

The suggested preparation process comprises reduction of a hydroxy ester of the general formula X, its bringing into reaction with an imine salt of the general formula XIII being prepared in situ by reacting thionyl chloride with dimethylformamide followed by subsequent reduction of the resulting halogenated compound by means of a suitable reducing agent giving rise of the ester of the general formula XII that is then brought, at a temperature ranging from 30 degC to 70 degC, into reaction with dimethylamine in a polyhydroxylated solvent.

Description

Technical field

The invention relates to a process for the preparation of Λζ N, 6-trimethyl-2- (4-methylphenyl) imidazo [1,2-a] pyridine-3-acetamide and its salts.

BACKGROUND OF THE INVENTION

AA6-Trimethyl-2- (4-methylphenyl) imidazo [1,2-a] pyridine-3-acetamide is a substance that is clinically manifested as a hypnotic [P. George et al., Actual. Chim. Ther. 18, 215 (1990), P. George et al. - Imidazopyridines in Sleep Disorders - De. J. P. Sauvanet, S.Z. Langer and P.L. Moselli Raven Press - New York, 1988, p. 11], which is characterized by the fact that it does not belong to the group of benzhodiazepines constituting to date the essence of most active substances (medicaments) with this activity.

This substance has the structural formula I

O)

Methods for the preparation of AV, 6-trimethyl-2- (4-methylphenyl) imidazo- [1,2-a] pyridine-3-acetamide of the general formula I [European patents EP 50563 and 251589 and French patent 2600650] are known, prepared by reacting imidazo [1,2-a] pyridine of formula II with acetal of the Λζ N-dimethylglyoxamides of formula III

RO, l |

C-CH - N _{(CH3) 2}

RO (ΠΙ) in which R is an alkyl group, to give the hydroxyamide of formula IV without going through the ester intermediate.

CON _(CH3) 2 (IV).

- 1 GB 292446 B6

SUMMARY OF THE INVENTION

The invention therefore relates to a process for the preparation of a compound of formula I which comprises reacting 2-amino-5-methylpyridine of formula V with 4-methylhaloacetophenone of formula VI to give 6-methyl-2- (4-methylphenyl) imidazo [ 1,2-a] pyridine of formula II.

H ₃ C

(IN)

—X (VII) (VI)

The first step of the reaction to obtain the 4-methylhaloacetophenone of formula VI from the acid halide of formula VII in which X is chlorine or bromine is carried out in toluene with the addition of a Lewis acid such as aluminum chloride or ferric chloride as a catalyst.

The temperature must be below 10 ° C.

The second step is carried out in an alkaline medium by adding a base, such as sodium bicarbonate or potassium bicarbonate, to a solvent to which an alcohol containing one to three carbon atoms is added.

The reaction temperature ranges from 40 to 70 ° C.

6-Methyl-2- (4-methylphenyl) imidazo [1,2-a] pyridine of formula II is reacted with methyl glyoxalate of formula VIII or a methyl hemiacetal of formula IX to give a hydroxyester of formula X.

CHO co ₂ ch ₃ (VIII) ^H0 = H-CO ₂ CH ₃ h ₃ co (IX)

(X)

-2GB 292446 B6

This reaction is carried out in a solvent which is a halogenated hydrocarbon, for example dichloromethane, chloroform, 1,2-dichloroethane or trichlorethylene, at a temperature of 40 to 70 ° C.

The hydroxyl group is removed by substitution with a chlorine atom via reaction with an imine salt prepared by the reaction of thionyl chloride and dimethylformamide. The resulting halogenated compound of formula XI is reduced to the ester of formula XII without isolation.

It should be noted that the intermediates of formula (X), (XI) and (XII) obtained in the process of preparing the compound of formula (I) according to the invention are novel and have not been described in the literature.

The compound of formula XI is prepared in a halogenated solvent such as dichloromethane, chloroform or 1,2-dichloroethane at a reaction temperature of 0 to 30 ° C. The reaction of a compound of formula XI to obtain a compound of formula XII is carried out in a solvent as described above by the addition of a reducing agent such as sodium hydrosulfide or sodium sulfoxylate-formaldehyde.

The reaction temperature must be between 10 and 50 ° C.

Reaction of a compound of formula XII with dimethylamine in a polyhydroxylated solvent, for example, ethylene glycol or propylene glycol, provides the amide of formula I.

The amide of formula I is converted into the corresponding salts by dissolving in an alcohol such as methanol, ethanol or isopropanol and adding an acid solution such as tartaric acid, oxalic acid or acetic acid in the same solvent. The molar ratio of added acid to amide ranges from 0.4: 1 to 1: 1.

In the above-described preparations of the invention, the use of the glyoxylic acid methyl ester of formula (Vin) or its methyl hemiacetal of formula (IX) is more advantageous than the use of a compound of formula (III).

The process of the invention also does not require the use of hazardous solvents such as isopropyl ether, nor does it require the isolation of the chlorinated compound of formula XI, which simplifies the entire manufacturing process.

Another important difference of the process according to the invention is the use of the chlorimine salt of formula XIII as a reagent to obtain the chlorestar of formula XI.

_{+ /} CH ₃ C-CH-N-CR (IX)

-3GB 292446 B6

This reagent can be used under milder and therefore more selective conditions, which is reflected in the overall performance and, in particular, in the purity of the products obtained. The amide of the formula I is obtained in the form of colorless crystals and 73% yield in the case of the transformation of the hydroxyester of the formula X to the ester of the formula XII.

The sodium sulfoxylate used to reduce the chlorinated intermediate of formula XI is a simpler and more economical reducing agent than sodium borohydride.

DETAILED DESCRIPTION OF THE INVENTION

The following examples, which are illustrative only, are not intended to limit the scope of the invention as defined by the appended claims.

Example 1

6-Methyl-2- (4-methylphenyl) imidazo [1,2a] pyridine (II)

Toluene (9.4 L) and aluminum chloride (3.10 kg) were charged into the 501 L reactor with stirring.

After the internal temperature of the slurry reached 0-5 ° C, a solution of α-bromoacetyl bromide (2 L) in toluene (2.8 L) was added to the slurry. The internal temperature was kept below 10 ° C. After the addition was complete, the internal temperature was maintained at a temperature range of 2 to 25 ° C for 45 minutes.

Water (13.2 L) was then slowly added such that the internal temperature did not exceed 50 ° C and stirring was continued for an additional hour. The phases were separated.

The aqueous phase was extracted again with toluene (3.6 L), the organic phases were combined and washed with water (5 L), 5% sodium bicarbonate solution (4 L), again with water (4 L) and finally with saturated sodium chloride solution (4 L). 1).

The product obtained was subjected to thin layer chromatography on silica gel with a fluorescent indicator, eluting with benzene and ethyl acetate 9: 1.

The obtained organic phase containing an intermediate of formula (VI) in which X is bromine was placed in a 501 liter reactor and heated to an internal temperature of about 30 ° C. Sodium bicarbonate (2.08 kg) and a solution of 2-amino-5-methylpyridine (2.63 kg) in methanol (4.5 L) were then added.

After the addition was complete, the suspension was heated to an internal temperature of 58-62 ° C and held at that temperature for 3 hours. The reaction mixture was analyzed by thin layer chromatography as described above.

After completion of the reaction, the suspension was cooled and vacuum filtered. The solid was rinsed with methanol (2 x 2.5 L and 1 x 1.5 L), followed by hot water (1 x 16.6 L) and water at room temperature (1 x 3 L). The product obtained was dried with a stream of air in an oven heated to 60 ° C until a constant weight was achieved, for a maximum of 10 hours.

3.8 g (70.2% yield) of a slightly yellowish crystalline solid, m.p. 208 DEG-208.5 DEG C., containing 99.3% of the title compound were obtained.

Δ-NMR (CDCl 3): δ (ppm): 7.83 (3H, d); 7.71 (1 H, s); 7.51 (1 H, d); 7.23 (2 H, d); 6.99 (1 H, dd); 2.38 (3 H, s); 2.30 (3 H, s).

-4GB 292446 B6

IR (KBr) (cm < -1 >):3131-2860;1645.5;1485.4;1423.7;1346.5;825.7;806.4; 735.0.

MS (70eV) m / e (%): 223 (16.3); 222 (100); 221 (18.9); 220 (3.4); 92 (5.9); 65 (5.1).

Example 2

6-Methyl-2- (4-methylphenyl) imidazo [1,2-a] pyridine-3- (α-hydroxy) methyl acetate (X)

To a 501 L reactor containing 1,2-dichloroethane (11 L) was added with stirring an intermediate of formula II (3.34 kg) followed by anhydrous sodium acetate (0.308 kg).

A solution of methyl glyoxalate VIII (1.6 kg) in 1,2-dichloroethane (5 L) was added to the obtained mixture with stirring.

The mixture was heated and heated until an internal temperature of 55 ° C was reached at which it was stirred for the next 3 hours. The reaction mixture was analyzed by thin layer chromatography on silica gel, eluting with ethyl acetate: cyclohexane (6: 4).

After completion of the reaction, the reaction mixture began to cool.

The cooled suspension was vacuum filtered to give a solid which was rinsed with 1,2-dichloromethane (1x 3.5 L and 1x 1.5 L) followed by water (1x 13.4 L) and 1x 3.4 L.

The product was dried in an air stream in an oven heated to 60 ° C until constant weight.

4.31 kg (92.5% yield) of a colorless solid are obtained with a melting point of 205 DEG C. at which decomposition occurs.

1 H-NMR (CDCl 3): δ (ppm): 7.99 (1H, s); 7.53 (2 H, d); 7.47 (1 H, d); 7.18 (2 H, d); 7.04 (1 H, d); 5.80 (1 H, s); 4.05 → 1.3 (1H, sa); 3.71 (3 H, s); 2.38 (3 H, s); 2.31 (3 H, s).

IR (KBr) (cm -1) ¹ : 3447.3; 1749.7; 1452.6; 1387.0; 1198.0; 1151.7; 1084.2; 823.7; 796.7.

MS (70eV) m / e (%): 311 (2.0); 310 (9.0); 252 (19.7); 251 (100); 223 (3.6); 222 (2.0); 103 (1/1); 92 (4.4); 65 (2.8).

Example 3

6-Methyl-2- (4-methylphenyl) imidazole [1,2-a] pyridine-3- (α-hydroxy) methyl acetate (X)

To a 600 liter reactor containing dichloromethane (2601) was added with stirring an intermediate of formula II (95 kg) followed by anhydrous sodium acetate (8.8 kg).

A solution of methyl glyoxalate IX (75 kg) (621) was then added with stirring at room temperature.

The reaction mixture was started to heat and warmed to 40-42 ° C and stirred at this temperature for the next 4 hours. The reaction mixture was analyzed by thin layer chromatography on silica gel, eluting with ethyl acetate: cyclohexane (6: 4).

After completion of the reaction, the reaction mixture was cooled to 5 ° C.

-5GB 292446 B6

The cooled suspension was then centrifuged and the resulting solid was washed with dichloromethane.

The product obtained was dried in a stream of air at room temperature. The solid was suspended in water (355 L) at 28 ° C. The resulting suspension was again centrifuged while rinsing with water. The product was dried with a stream of air at 60 ° C. 121.4 kg (91.5% yield) of a product having the same properties as the product of Example 2 was obtained.

Example 4

6-Methyl-2- (4-methylphenyl) imidazo [1,2-a] pyridine-3-methyl acetate (XII)

Chloroform (9.6 L) and thionyl chloride (2.02 L) were charged to a 501 L reactor. The contents of the reactor were cooled to 5 ° C and a solution of dimethylformamide (2.0 L) in chloroform (4.0 L) was added with stirring. The reaction was exothermic and the reaction mixture reached room temperature.

At this temperature, the reaction mixture was stirred for 45 minutes, measured from the time when the addition of the individual substances to the reactor had begun.

The reaction mixture was cooled to an internal temperature of 5 ° C to 10 ° C and an intermediate of formula X (6.0 kg) was added in large portions along with additional chloroform (3.3 L) with stirring.

Stirring was continued at room temperature for a further 2 hours.

Sodium sulfoxylate-aldehyde (Rongalite) was then added in large portions and stirring was continued at 38-40 ° C for a further 2 hours.

The reaction mixture was heated to 50 ° C, methanol (20 L) was added, the reaction mixture was filtered at this temperature 30, and the precipitate was rinsed with methanol.

The filtrate was concentrated by distillation under reduced pressure to a volume of approximately 13 L while removing chloroform with methanol.

Then water (6 L) was added and the mixture was heated to 60 ° C. After filtration, the filtrate was cooled to 40 ° C and 10% sodium hydroxide (w / v) was added to the cooled filtrate to adjust the pH to 10-11.

The product was cooled and filtered.

This crude wet and solid was crystallized with methanol (20 L) by hot filtration through charcoal (0.1 kg), water (19 L) was added and the mixture was cooled.

The product obtained was dried by a stream of air in an oven where the temperature was raised up to 60 ° C.

This gave 4.16 kg (73.1% yield) of a solid with a melting point of 133-135 ° C.

1 H-NMR (CDCl ₃ ): δ (ppm): 7.83 (1H, s); 7.70 (2 H, d); 7.55 (1 H, d); 7.27 (2 H, d); 7.0 (1 H, dd); 4.02 (2 H, s); 3.76 (3 H, s); 2.40 (3 H, s); 2.35 (3 H, s).

IR (KBr) (cm -1) ¹ : 1726.6; 1392.8; 1331.1; 1228.8; 1176.8.

MS (70eV) m / e (%): 296 (2.0); 295 (14.0); 294 (65.5); 237 (3.9); 236 (42.6); 235 (100); 233 (10.4); 221 (2.0); 220 (11.5); 219 (20.7); 92 (31.2); 86 (8.0); 84 (11.2); 65 (16).

-6GB 292446 B6

Example 5

7V, N, 6-Trimethyl-2- (4-methylphenyl) imidazo [1,2-a] pyridine-3-acetamide (I)

In a 50 liter stainless steel reactor, which was designed to operate at elevated pressure and containing a 39% dimethylamine solution in ethylene glycol (w / w) (7.61), was slowly added with stirring the intermediate of formula XII ( 3.125 kg).

The product was sealed and heated to 55-65 ° C so that the pressure did not exceed 24.1 x ^{10 4} Pa.

After three hours, thin-layer chromatography (silica gel plates with fluorescent indicator; eluent: cyclohexane: methyl chloride: diethylamine (7: 2: 1)) verified the completion of the reaction.

The slurry was cooled until the reactor pressure was removed and then poured over water (121) contained in a stainless steel vessel equipped with a mechanical stirrer. An additional 4 L of water was poured into the vessel and the reactor was cleaned. The suspension was stirred at room temperature for 2 hours.

The suspension was cooled to 10 ° C, filtered and washed with water (2 x 3 L).

The product obtained was dried in an air stream at 60 ° C until it reached a constant weight.

The crude solid was recrystallized from acetonitrile (171).

The product obtained was cooled, filtered, rinsed and dried in an oven heated to 60 ° C with a stream of air until a constant weight was reached

Thus 2.84 g (87% yield of a colorless product with a melting point of 195-197 ° C) are obtained.

1 H-NMR (CDCl 3): δ (ppm): 7.98 (1H, s); 7.55 (2 H, d); 7.52 (1 H, d); 7.26 (2 H, d); 7.04 (1 H, dd); 4.07 (2 H, s); 2.94 (3 H, s); 2.88 (3 H, s); 2.40 (3 H, s); 2.35 (3 H, s).

¹³ CNMR (CDCl 3) (with broad band decalculation of H 1): 166.161; 143.959; 143.682; 137.187; 131.717; 129.139; 128.217; 127.230; 121.99; 121.449; 116.355; 113.560; 37.288; 35.632; 29.973; 21.079; 18,249.

IR (KBr) (cm -1) ¹ : 2980-3005; 1635.9; 1138.2; 825.7; 794.8.

MS (70eV) m / e (%): 309 (5.0); 308 (41.2); 307 (100); 236 (68.2); 235 (71.9); 233 (22.9); 222 (2.1); 221 (4.8); 220 (27.4); 219 (51.4); 92 (51.6); 65 (37.9).

Elementary analysis:

Found: C: 74.36% H: 6.92% N: 13.56%

Calculated: C: 74.24% H: 6.89% N: 13.67%

Example 6

N, N, 6-Trimethyl-2- (4-methylphenyl) imidazo [1,2-a] pyridine-3-acetamide- [R- (R *, R *)] - 2,3-dihydroxybutanedioate (2: 1)

-7EN 292446 B6

To a 501 liter methanol-filled reactor (25 L) was added the compound of formula I (2.44 kg).

The reaction mixture was heated until all solids had dissolved and a solution of Z - (+) - tartaric acid (0.6 kg) in methanol (4.5 L) was added to the obtained solution.

The product obtained was concentrated by distillation to a volume of approximately 181, cooled and filtered, washing with the same solvent.

The product was dried in an air stream whose temperature gradually increased to about 60 ° C.

This gave 2.82 kg (93% yield) of the reference compound with a melting point of 193-195 ° C at which decomposition occurred.

IR (KBr) (anhydrous form) (cm ^-1 ): 16.45.5; 1404.4; 1344.6; 1275.1; 1147.8; 1138.2; 1115.0; 1076.4; 1022.4; 918.3; 825.7; 794.8; 719.6; 621.2; 600.0.

Elementary analysis:

Found: C: 66.06% H: 6.32% N: 10.95% Calculated: C: 65.97% H: 6.28 N: 10.99%

PATENTOVÉ

Claims (5)

Claims Process for the preparation of N, N, 6-trimethyl-2- (4-methylphenyl) imidazo [1,2-a] pyridine-3-acetamide of formula I a) wherein the hydroxy ester of formula X (X) treated with an iminium salt of formula XIII _{+ /} CH ₃ D-CH-N-Cl (ΧΠΙ) / prepared in situ by reaction of thionyl chloride with dimethylformamide and subsequent reduction of the resulting halogen compound with a suitable reducing agent is prepared and subsequently reacted at 30 ° C to 70 ° C with dimethylamine in a polyhydroxylated solvent to form the acetamide of formula (I). A process according to claim 1, characterized in that a reducing agent selected from sodium sulfoxylate-formaldehyde or sodium bisulfite is used as a suitable reducing agent for the preparation of the ester (XII) and the resulting ester is reacted with dimethylamine in a polyhydroxylated solvent such as ethylene glycol or propylene glycol. 3. The method of claim 1 wherein said 6-methyl-2- ( 4-Methylphenyl) imidazo [1,2-a] pyridine-3- (α-hydroxy) methyl acetate of formula X is obtained by reacting a compound of formula II with methyl glyoxalate of formula VIII CHO ₂ CH ₃ (VIII) or a methyl hemiacetal thereof of formula IX -9EN 292446 B6 HO ^X CH-CO ₂ CH ₃ H.CO ⁷ (IX) in a chlorinated solvent such as chloroform, 1,2-dichloroethane or trichlorethylene at a temperature of 40 to 70 ° C. 4. A process according to claim 3 wherein the 6-methyl-2- (4-methylphenyl) imidazo [1,2-a] pyridine of formula II is the reaction product of the reaction of 2-amino-5-methylpyridine of formula V H ₃ C (V) and α-halo-4-methylacetophenone of general formula VI ch ₂ x (VI) Wherein X is Cl or Br, which is carried out in toluene and a C 1 -C 3 alcohol by the addition of a base such as sodium bicarbonate or potassium bicarbonate at a reaction temperature of 40 to 70 ° C. 5. A process for the preparation of an acetamide salt of the formula I, characterized in that the free base of the formula I is reacted with an acid such as tartaric acid, oxalic acid or acetic acid in an alcohol such as methanol, ethanol or isopropanol as solvent. wherein the molar ratio of acid to base ranges from 0.4: 1 to 1: 1, and the salt obtained is crystallized in 20 with a degree of purity suitable for use in human medicine.